Iron Overload in Diabetic Retinopathy: A Cause or a Consequence of Impaired Mechanisms?

Experimental Diabetes Research ◽

10.1155/2010/714108 ◽

2010 ◽

Vol 2010 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Andreea Ciudin ◽

Cristina Hernández ◽

Rafael Simó

Keyword(s):

Diabetic Retinopathy ◽

Iron Overload ◽

Iron Homeostasis ◽

Cell Function ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Renin Angiotensin System ◽

Retinal Neurodegeneration ◽

Novel Therapeutic Strategies

Iron is an essential ion for life, playing a central role in many metabolic processes. The most important property of free iron is its capacity to be reversibly oxidized and reduced, but at same time this make it highly pro-oxidant molecule. In this regard, iron is able to generate powerful reactive oxygen species (ROS). For this reason, careful control on iron availability is central to the maintenance of normal cell function in the retina. In the diabetic eye there is an impairment of iron homeostasis, thus leading to iron overload. The mechanisms involved in this process include: (1) Destruction of heme molecules induced by hyperglycemia (2) Intraretinal and vitreal hemorrhages (3) Overexpression of the renin-angiotensin system. The main consequences of iron overload are the following: (1) Retinal neurodegeneration due to the increase of oxidative stress (2) Increase of AGE-RAGE binding (3) Defective phagocytosis of retinal pigment epithelium, which generates the accumulation of autoantigens and the synthesis of proinflammatory cytokines. Further studies addressed to explore not only the role of iron in the pathogenesis of diabetic retinopathy, but also to design novel therapeutic strategies based on the regulation of iron homeostasis are needed.

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Histamine causes an imbalance between pro-angiogenic and anti-angiogenic factors in the retinal pigment epithelium of diabetic retina via H4 receptor/p38 MAPK axis

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001710 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001710

Author(s):

Byung Joo Lee ◽

Hye Eun Byeon ◽

Chang Sik Cho ◽

Young Ho Kim ◽

Jin Hyoung Kim ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Retinal Pigment Epithelium ◽

Regulatory Mechanism ◽

Histidine Decarboxylase ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Angiogenic Factors ◽

Mitogen Activated Protein Kinase ◽

Patients With Diabetes

IntroductionSystemic histaminergic activity is elevated in patients with diabetes mellitus. There are a few studies suggesting that histamine is implicated in the pathogenesis of diabetes, but the exact role of histamine in the development of diabetic retinopathy is unclear. The aim of this study was to investigate the role of histamine receptor H4 (HRH4) in the regulation of retinal pigment epithelium (RPE)-derived pro-angiogenic and anti-angiogenic factors under diabetic conditions.Research design and methodsThe levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), histamine and histidine decarboxylase (HDC) in the serum and vitreous samples of patients with diabetes were compared with those of patients without diabetes. The effect of hyperglycemia on expression levels of HRH4, VEGF, IL-6 and pigment epithelium-derived factor (PEDF) in the RPE was determined. The role of HRH4 in high glucose-induced regulation of VEGF, IL-6 and PEDF in ARPE-19 cells and the underlying regulatory mechanism were verified using an RNA interference-mediated knockdown study.ResultsThe serum and vitreous levels of VEGF, IL-6, histamine and HDC were more increased in patients with diabetic retinopathy than in patients without diabetes. HRH4 was overexpressed in RPE both in vitro and in vivo. Histamine treatment upregulated VEGF and IL-6 and downregulated PEDF expression in ARPE-19 cells cultivated under hyperglycemic conditions. Hyperglycemia-induced phosphorylation of p38 and subsequent upregulation of VEGF and IL-6 and downregulation of PEDF were dampened by small interfering RNA-mediated knockdown of HRH4 in ARPE-19 cells.ConclusionsTaken together, HRH4 was a critical regulator of VEGF, IL-6 and PEDF in the RPE under hyperglycemic conditions and the p38 mitogen-activated protein kinase pathway mediated this regulatory mechanism.

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Role of Peoxisome Proliferator Activator Receptor on Blood Retinal Barrier Breakdown

PPAR Research ◽

10.1155/2008/679237 ◽

2008 ◽

Vol 2008 ◽

pp. 1-4 ◽

Cited By ~ 6

Author(s):

Yasuo Yanagi

Keyword(s):

Diabetic Retinopathy ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Critical Role ◽

Blood Retinal Barrier ◽

Early Diabetes ◽

Pathological Conditions ◽

Barrier Breakdown ◽

Brb Breakdown

The retinal vessels have two barriers: the retinal pigment epithelium and the retinal vascular endothelium. Each barrier exhibits increased permeability under various pathological conditions. This condition is referred to as blood retinal barrier (BRB) breakdown. Clinically, the most frequently encountered condition causing BRB breakdown is diabetic retinopathy. In recent studies, inflammation has been linked to BRB breakdown and vascular leakage in diabetic retinopathy. Biological support for the role of inflammation in early diabetes is the adhesion of leukocytes to the retinal vasculature (leukostasis) observed in diabetic retinopathy. is a member of a ligand-activated nuclear receptor superfamily and plays a critical role in a variety of biological processes, including adipogenesis, glucose metabolism, angiogenesis, and inflammation. There is now strong experimental evidence to support the theory that inhibits diabetes-induced retinal leukostasis and leakage, playing an important role in the pathogenesis of diabetic retinopathy. Therapeutic targeting of may be beneficial to diabetic retinopathy.

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A Possible Role of Acrolein in Diabetic Retinopathy: Involvement of a VEGF/TGFβ Signaling Pathway of the Retinal Pigment Epithelium in Hyperglycemia

Current Eye Research ◽

10.3109/02713683.2012.713152 ◽

2012 ◽

Vol 37 (11) ◽

pp. 1045-1053 ◽

Cited By ~ 21

Author(s):

Jeffery Grigsby ◽

Brandi Betts ◽

Eileen Vidro-Kotchan ◽

Richard Culbert ◽

Andrew Tsin

Keyword(s):

Diabetic Retinopathy ◽

Retinal Pigment Epithelium ◽

Signaling Pathway ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Tgfβ Signaling ◽

Tgfβ Signaling Pathway

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The photoreceptor cytoskeleton visualized

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100122800 ◽

1992 ◽

Vol 50 (1) ◽

pp. 480-481

Author(s):

Beth Burnside

Keyword(s):

Outer Segment ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Cell Polarization ◽

Synaptic Proteins ◽

Cell Functions ◽

Vertebrate Photoreceptor ◽

Numerous Cell ◽

Turn Over

The vertebrate photoreceptor provides a drammatic example of cell polarization. Specialized to carry out phototransduction at its distal end and to synapse with retinal interneurons at its proximal end, this long slender cell has a uniquely polarized morphology which is reflected in a similarly polarized cytoskeleton. Membranes bearing photopigment are localized in the outer segment, a modified sensory cilium. Sodium pumps which maintain the dark current critical to photosensory transduction are anchored along the inner segment plasma membrane between the outer segment and the nucleus.Proximal to the nucleus is a slender axon terminating in specialized invaginating synapses with other neurons of the retina. Though photoreceptor diameter is only 3-8u, its length from the tip of the outer segment to the synapse may be as great as 200μ. This peculiar linear cell morphology poses special logistical problems and has evoked interesting solutions for numerous cell functions. For example, the outer segment membranes turn over by means of a unique mechanism in which new disks are continuously added at the proximal base of the outer segment, while effete disks are discarded at the tip and phagocytosed by the retinal pigment epithelium. Outer segment proteins are synthesized in the Golgi near the nucleus and must be transported north through the inner segment to their sites of assembly into the outer segment, while synaptic proteins must be transported south through the axon to the synapse.The role of the cytoskeleton in photoreceptor motile processes is being intensely investigated in several laboratories.

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A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface

Communications Biology ◽

10.1038/s42003-021-01682-5 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Cynthia Tang ◽

Jimin Han ◽

Sonal Dalvi ◽

Kannan Manian ◽

Lauren Winschel ◽

...

Keyword(s):

Photoreceptor Cell ◽

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Cell Loss ◽

Human Model ◽

Lysosomal Storage ◽

Rpe Cells ◽

Cln3 Disease

AbstractMutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS) by retinal pigment epithelium (RPE) cells, a cellular process essential for photoreceptor survival. Specifically, a proportion of CLN3 in human, mouse, and iPSC-RPE cells localized to RPE microvilli, the site of POS phagocytosis. Furthermore, patient-derived CLN3 disease iPSC-RPE cells showed decreased RPE microvilli density and reduced POS binding and ingestion. Notably, POS phagocytosis defect in CLN3 disease iPSC-RPE cells could be rescued by wild-type CLN3 gene supplementation. Altogether, these results illustrate a novel role of CLN3 in regulating POS phagocytosis and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy.

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The Role of Imaging in Planning Treatment for Central Serous Chorioretinopathy

Pharmaceuticals ◽

10.3390/ph14020105 ◽

2021 ◽

Vol 14 (2) ◽

pp. 105

Author(s):

Stefano Da Pozzo ◽

Pierluigi Iacono ◽

Alessandro Arrigo ◽

Maurizio Battaglia Parodi

Keyword(s):

Central Serous Chorioretinopathy ◽

Therapeutic Strategy ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Subretinal Fluid ◽

Subretinal Space ◽

Planning Treatment ◽

Multiple Biomarkers ◽

Effective Procedures

Central serous chorioretinopathy (CSC) is a controversial disease both in terms of clinical classification and choice of therapeutic strategy. Choroidal layers, retinal pigment epithelium (RPE), photoreceptors, and retina are involved to varying degrees. Beyond well-known symptoms raising the clinical suspect of CSC and slit-lamp fundus examination, multimodal imaging plays a key role in assessing the extent of chorioretinal structural involvement. Subretinal fluid (SRF) originating from the choroid leaks through one or multiple RPE defects and spreads into the subretinal space. Spontaneous fluid reabsorption is quite common, but in some eyes, resolution can be obtained only after treatment. Multiple therapeutic strategies are available, and extensive research identified the most effective procedures. Imaging has carved a significant role in guiding the choice of the most appropriate strategy for each single CSC eye. Multiple biomarkers have been identified, and all of them represent a diagnostic and prognostic reference point. This review aims to provide an updated and comprehensive analysis of the current scientific knowledge about the role of imaging in planning the treatment in eyes affected by CSC.

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Association of Thiol–disulfide Homeostasis with Retinal Layer Thickness in Patients with Diabetes Mellitus

10.21203/rs.3.rs-791653/v1 ◽

2021 ◽

Author(s):

Muhammet Cuneyt Bilginer ◽

Abbas Ali Tam ◽

Berna Evranos Ogmen ◽

Bagdagul Yuksel Guler ◽

Nagihan Ugurlu ◽

...

Keyword(s):

Diabetes Mellitus ◽

Diabetic Retinopathy ◽

Layer Thickness ◽

Disease Duration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Control Group ◽

Retinal Layer ◽

Healthy Controls ◽

Total Thiol

Abstract Background: This study aimed to investigate the relationship between early changes in retinal layer thickness and thiol–disulfide homeostasis in patients with type II diabetes mellitus (T2DM).Materials-Methods: There were 69 patients with T2DM (61 patients without retinopathy, 8 patients with retinopathy) and 21 healthy controls. In patients without retinopathy, 31 of the patients had a disease duration under 10 years, 30 of the patients had a disease duration over 10 years. Retinal layer thickness of the right eye was measured using Spectral Domain Optical Coherence Tomography. Results: Patients with T2DM and healthy controls had mean ages of 48.40 ± 8.25 years and 45.94 ± 7.32 years, respectively. The ganglion cell layer and retinal pigment epithelium thicknesses were significantly lesser in patients without diabetic retinopathy than those in the control group. In patients without diabetic retinopathy and with a disease duration of under 10 years, there was a negative correlation between the retinal nerve fiber layer thickness (µm) and disulphide/total thiol ratio, between the inner nuclear layer thickness (µm) and disulphide/native thiol ratio as well as disulphide/total thiol ratio (r= −0.376, p= 0.037; r= −0.356, p= 0.050; r= −0.380, p= 0.035, respectively) and positive correlation between the INL thickness (µm) and native thiol/total thiol ratio (r= 0.359, p= 0.047).Conclusion: Early changes in retinal layers in patients with DM were associated with thiol–disulfide homeostasis. Administration of therapeutic supplements may aid in the management of low thiol concentrations; this increases the importance of the study findings.

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The Impact of Glycemic Control on Retinal Photoreceptor Layers and Retinal Pigment Epithelium in Patients With Type 2 Diabetes Without Diabetic Retinopathy: A Follow-Up Study

Frontiers in Endocrinology ◽

10.3389/fendo.2021.614161 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fukashi Ishibashi ◽

Aiko Kosaka ◽

Mitra Tavakoli

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Retinal Pigment Epithelium ◽

Glycemic Control ◽

Pigment Epithelium ◽

Outer Nuclear Layer ◽

Retinal Pigment ◽

Glycemic Variability ◽

Hba1c Levels

AimsTo establish the sequential changes by glycemic control in the mean thickness, volume and reflectance of the macular photoreceptor layers (MPRLs) and retinal pigment epithelium in patients with type 2 diabetes without diabetic retinopathy.MethodsThirty-one poorly controlled (HbA1c > 8.0%) patients with type 2 diabetes without diabetic retinopathy undergoing glycemic control and 39 control subjects with normal HbA1c levels (< 5.9%) underwent periodical full medical, neurological and ophthalmological examinations over 2 years. Glycemic variability was evaluated by standard deviation and coefficient of variation of monthly measured HbA1c levels and casual plasma glucose. 3D swept source-optical coherence tomography (OCT) and OCT-Explorer-generated enface thickness, volume and reflectance images for 9 subfields defined by Early Treatment Diabetic Retinopathy Study of 4 MPRLs {outer nuclear layer, ellipsoid zone, photoreceptor outer segment (PROS) and interdigitation zone} and retinal pigment epithelium were acquired every 3 months.ResultsGlycemic control sequentially restored the thickness and volume at 6, 4 and 5 subfields of outer nuclear layer, ellipsoid zone and PROS, respectively. The thickness and volume of outer nuclear layer were restored related to the decrease in HbA1c and casual plasma glucose levels, but not related to glycemic variability and neurological tests. The reflectance of MPRLs and retinal pigment epithelium in patients was marginally weaker than controls, and further decreased at 6 or 15 months during glycemic control. The reduction at 6 months coincided with high HbA1c levels.ConclusionGlycemic control sequentially restored the some MPRL thickness, especially of outer nuclear layer. In contrast, high glucose during glycemic control decreased reflectance and may lead to the development of diabetic retinopathy induced by glycemic control. The repeated OCT examinations can clarify the benefit and hazard of glycemic control to the diabetic retinopathy.

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Effects of refraction and axial length on the development and progression of diabetic retinopathy

Clinical ophthalmology ◽

10.32364/2311-7729-2021-21-4-205-209 ◽

2021 ◽

Vol 21 (4) ◽

pp. 205-209

Author(s):

M.M. Bikbov ◽

◽

O.I. Orenburkina ◽

A.E. Babushkin ◽

A.A. Fakhretdinova ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Diabetic Retinopathy ◽

Growth Factor ◽

Axial Length ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Vascular Endothelial ◽

Keywords Diabetic Retinopathy ◽

Eye Disorders ◽

Endothelial Growth Factor

Eye disorders have a special place in diabetes since visual impairment has a significant effect on the quality of life. Therefore, determining risk factors and prognostic criteria for disease course are essential for developing strategies for early prevention of diabetic retinopathy (DR). This paper addresses studies on various aspects of DR in patients with myopia. It was demonstrated that DR arises, develops, and progresses in different ways under various axial lengths (AL). Thus, many authors report that DR barely occurs in high myopia. Some of them account for this phenomenon for poor blood circulation in a long myopic eye. Others refer to a significantly lower vascular endothelial growth factor (VEGF) concentration in longer eyes or eyes with myopic refraction. The third authors argue a focal disintegration of retinal pigment epithelium to eliminate metabolic end products through the choroid and sclera. As a result, neither acidosis nor venous congestion develops, and endothelial barrier function remains unaffected Keywords: diabetic retinopathy, myopia, axial length, vascular endothelial growth factor, emmetropia, hyperopia, diabetes. For citation: Bikbov M.M., Orenburkina O.I., Babushkin A.E., Fakhretdinova A.A. Effects of refraction and axial length on the development and progression of diabetic retinopathy. Russian Journal of Clinical Ophthalmology. 2021;21(4):205–209 (in Russ.). DOI: 10.32364/2311-7729- 2021-21-4-205-209.

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